1. Field of the Invention
This invention relates to novel alkyl, benzyl or phenyl 3-oxoandrost-4-ene 17 beta-thiocarboxylates and the corresponding androsta-1,4-dienes. More specifically it relates to anti-inflammatory 16 alpha,17 alpha-acetonides and 17 alpha-hydroxy-16-methyl compounds which are substituted at the 4 position with fluoro, chloro or bromo and are optionally substituted at the 6 position with fluoro or chloro. The invention further relates to pharmaceutical anti-inflammatory compositions comprising a compound of the invention in combination with a pharmaceutically acceptable excipient. This invention even further relates to a process for the preparation of these novel compounds.
2. Prior Art
Certain 3-oxoandrost-4-ene 17 beta-carboxylic acids which are substituted at the 9 position with chlorine or fluorine and at the 11 position with keto or hydroxy or chloro group are known. See for example U.S. Pat. No. 3,828,080. It is known that 3-oxoandrost-4-ene 17 beta-carboxylic acids may be substituted at both the 9 alpha and 6 alpha positions with fluoro. See for example U.S. Pat. No. 3,636,010.
It is also known from U.S. Pat. No. 3,989,686 to Phillipps et al. of Glaxo that steroids of formula (II)
wherein
R.sup.1 is H or CH.sub.3 ; PA1 R.sup.2 is H or CH.sub.3 ; PA1 R.sup.3 is H or, when R.sup.2 is H, C.sub.1-6 alkoxy, C.sub.1-5 alkyl, thiocyanato or halogen; PA1 R.sup.4 is H or CH.sub.3 ; PA1 R.sup.5 is C.sub.1-6 alkyl optionally substituted by halo or NR.sup.6 R.sup.7, where R.sup.6 and R.sup.7 are the same or different, C.sub.1-6 alkyl or R.sup.6 and R.sup.7 together with N are morpholino, thiamorpholine or morpholino substituted with C.sub.1-6 alkyl; and PA1 the dotted lines in the "A" ring represent an optional double bond at these positions. These compounds are useful as anesthetics. PA1 Z is sulfur; PA1 X.sup.1 is fluoro, chloro or bromo; PA1 X.sup.2 is fluoro, chloro or hydrogen; PA1 X.sup.3 is fluoro, chloro, bromo or hydrogen; ##STR1## when X.sup.3 may also be chloro; R is alkyl of 1 through 6 carbon atoms or phenyl or benzyl optionally substituted with 1 substituent chosen from the group consisting of alkyl of 1 through 4 carbon atoms, alkoxy of 1 through 4 carbon atoms and halo; PA1 R.sup.1 is hydrogen or alkanoyl of 2 through 6 carbon atoms when R.sup.2 is hydrogen, alpha-methyl or beta-methyl or OR.sup.1 and R.sup.2 together represent 16 alpha, 17 alpha-isopropylidenedioxy; and PA1 the dotted line between C-1 and C-2 represents an optional double bond.
Methyl 3 beta-acetoxyallothiol-cholonate and methyl 3 beta-acetoxy-etiothiolchol-5-enate are also known compounds. See, e.g., Jerger et al., Helv. Chem. Acta. 29, 684-92 (1946).
A heretofore unknown series of 3-oxoandrost-4-ene 17 beta-thiocarboxylates being substituted at the 4 position with fluoro, chloro or bromo and optionally substituted at the 6 position with fluoro or chloro has been discovered and is disclosed herein. The compounds exhibit good anti-inflammatory activity and few adverse side effects.